It is well established that post-operative adhesions develop in the vast majority of patients after surgery. Injury or inflammation in the peritoneal cavity produces a fibrous exudate. As a result, the serosal surfaces stick together. The fibrous exudate may be absorbed or invaded by fibroblasts to form a permanent fibrous adhesion.
Removal of fibrin before it is invaded by fibroblasts prevents the formation of permanent fibrous adhesions. Removal of fibrin occurs due to the fibrinolytic activity of the peritoneal cavity. Fibrinolytic activity can vary as a result of surgery. Fibrinolytic activity is absent from a peritoneal wound during the first 48 hours after surgery. However, there is a gradual increase after this time up to 8 days when the peritoneum heals. The source of the fibrinolytic activity is found in the mesothelial cells. It is postulated that the absence of definitive mesothelial cells with their associated fibrinolytic activity may facilitate adhesion formation by allowing fibroplasm to occur before definitive mesothelial cells have grown between and separated the two opposed surfaces of a fibrinous adhesion.
The molecular events underlying peritoneal wound healing and development of fibrous adhesions are complex and multifactoral. The cascade of events that leads to peritoneal wound repair in many aspects resembles those that occur during skin wound healing, which is characterized by inflammation, cellular migration, proliferation, phenotypic differentiation and tissue remodeling. Tissue remodeling involves deposition and degradation of the extracellular matrix which are highly regulated processes, occurs throughout wound repair, and are influenced by a host of locally expressed growth factors, cytokines and eicosanoids. The extracellular matrix is a dynamic component capable of modulating various cellular activities including cell—cell interaction, proliferation, differentiation and sequestering potent biological response modifiers from the wound environment. In addition, it has become clear that excess production and deposition of the extracellular matrix is a key factor in producing tissue fibrosis throughout the body including the development of peritoneal adhesions.
It has been suggested that serine proteases and metalloproteinases not only play a critical role in various stages of normal wound repair, but are involved in enhanced breakdown of the major components of the extracellular matrix in pathological wound healing. Matrix metalloproteinases (“MMPs”) are members of a family of zinc proteases which hydrolyze various components of the extracellular matrix such as collagens, fibronectin, laminin, elastin and protoglycans. Seventeen different MMPs have been isolated and characterized, which based on their substrate specificity are divided into several subgroups: collagenases (MMP-1, MMP-8, MMP-13), gelatineses (MMP-2 and MMP-9), stromalysins (MMP-3, MMP-7, MMP-10, MMP-11), matrilysins (MMP-9), and the newly discovered membrane-type MMPs (MT-MMP1 to MT-MMP-4 or MMP-14 to MMP-17). The catalytic activity of MMPs is regulated at least in part by a group of proteins referred to as tissue inhibitors of matrix metalloproteineases or TIMPs. Four TIMPs have been identified and are referred to as TIMP-1, TIMP-2, TIMP-3 and TIMP-4.
A coordinated expression and balance between the production of MMPs and TIMPs is an important step in tissue remodeling. In general, MMPs are not expressed constitutively in vivo in adult tissues, but they are induced in response to various stimuli including proinflammatory cytokines, growth factors and hormones. MMPs are also induced in tissues that normally undergo extensive remodeling such as the endometrium during the menstrual cycle and wounds during healing. Furthermore, an important feature of the MMPs is that they are produced as inactive proenzymes and require activation, which is achieved by various factors including several serine proteineases such as plasmin, trypsin and neutrophil elastase. In contrast, the expression of TIMPs is wide spread in many tissues and is regulated in co-ordination with MMPs. TIMP-1 and TIMP-2 inhibit the activity of all MMPs by forming a high affinity complex in a 1:1 ratio. In addition to inhibiting the MMPs activity, TIMPs have also been shown to have growth factor like activity by stimulating cell growth.
Thus, for normal peritoneal healing to occur, the availability of these molecules must be optimal, precise, and synchronized. Inhibition, interruption, or excess expression of these molecules seems to be responsible for failure in normal healing, resulting in either impairment or excess tissue formation (adhesion development). Although the role of growth factors, cytokines, eicosanoids and serine proteinases have been investigated in relation to peritoneal wound repair and adhesion formation, there is no information currently available in respect to the expression of MMPs and TIMPs in the peritoneal environment.
The formation of intraperitoneal fibrous adhesions is a complex process that involves migration and mitosis of a variety of cell types, including inflammatory cells, mesothelial cells, and fibroblasts. Peptide growth factors and their receptors may play key roles in regulating many aspects of adhesion formation. Growth factors, such as epidermal growth factor (EGF), and transforming growth factor-β(TGF-β) may directly influence adhesion formation.